Calcium promotes α-synuclein liquid-liquid phase separation to accelerate amyloid aggregation.

α-Synuclein (α-Syn) is an aggregation-prone protein whose accumulation in Lewy bodies leads to neurodegenerative diseases like Parkinson's disease (PD). Calcium plays a critical role in neurons, and calcium dysregulation is one of the risk factors of PD. It is known that Ca2+ interacts with α-Syn and affects its assembly. However, how Ca2+ regulates α-Syn aggregation remains unclear. Here, we reported that Ca2+ accelerates α-Syn amyloid aggregation through the modulation of protein phase separation. We observed that Ca2+ promotes the formation of α-Syn liquid droplets but does not change the protein fluidity inside the droplets. Further studies showed Ca2+-involved α-Syn droplets are still able to fuse. A metal chelator eliminated Ca2+-induced enlargement of α-Syn droplets, suggesting the influence of Ca2+ on α-Syn assembly could be reversed at the stage of liquid-liquid phase separation (LLPS). Interestingly, our data showed Ca2+ still promoted α-Syn phase separation in the presence of the lipid membranes. In addition, Ca2+/α-syn droplets could efficiently recruit lipid vesicles to the surface of these condensates. Our findings demonstrate that Ca2+ facilitates α-Syn phase separation to accelerate amyloid aggregation and pave the path for understanding the implications of Ca2+ in α-Syn accumulation and PD.